Because we observed that some patients treated with immunotoxins developed anti-tumor immunity, we have developed a syngeneic mouse tumor model to study interactions of the immune system with immunotoxin therapy. We have developed syngeneic mouse models to evaluate the combination of LMB-100 and check point inhibitors. We find that the direct injection of LMB-100 into tumors synergizes with anti-CTLA-4 given I.P. to produce complete tumor regressions and the development of anti-tumor immunity. These studies were done in a mouse breast cancer model and are being extended to other cancer types to determine how general the effect is. We are also evaluating other check point inhibitors. Based on these studies a clinical trial combining LMB-100 with a check point inhibitor is being planned to open at NCI this year in mesothelioma and lung cancer. To develop a new treatment for myeloma we have made new immunotoxins targeting BCMA that is expressed on almost all myelomas. To evaluate these immunotoxins in a relevant animal model, we produced myeloma cells expressing luciferase and grow them in mouse bone marrow. We find the anti-BCMA immunotoxins are very active in 2 models of myeloma. NIH has licensed this program to a company that will produce immunotoxin for clinical trials. Previous studies have shown that immunotoxins cause immunogenic cell death. We have developed a mouse mesothelioma model using Balb/c mice in order to evaluate the best check point inhibitors to combine with LMB-100. We have made AB1 cells that express human mesothelin and grow them in the peritoneal cavity of Balb/c mice that are transgenic for human mesothelin.